In response to exercise or other stresses, catecholamines are released into the circulation and within the heart. Catecholaminergic stimulation of ß1-adrenergic receptors (ß1ARs) in the heart increases heart rate (chronotropy) and contractility (inotropy), resulting in increased cardiac output during acute stress. Concurrent stimulation of ß2-ARs dilates blood vessels, which increase blood flow to exercising muscles, thereby matching increased cardiac output to metabolic demands of the organs.

The inotropic mechanisms investigated by Valdivia and colleagues1 in the current issue of Circulation Research are essential for the acute stress-dependent increase of cardiac output. Each of the millions of muscle cells in the heart (cardiomyocytes) contribute to myocardial force development. Cardiomyocyte contraction is controlled by intracellular Ca2 release through a process called excitationcontraction coupling (ECC) that involves the following steps:(1) an action potential (AP) depolarizes the cell membrane;(2) voltage-dependent plasma membrane L-type calcium channels (Cav1. 2) opening results in a whole-cell inward Ca2 current (ICa);(3) ICa activates cardiac ryanodine receptor (RyR2)/Ca2 release channels located on the junctional sarcoplasmic reticulum (jSR), a process referred to as Ca2-induced Ca2 release (CICR);(4) Ca2 binds to troponin C (TnC) leading to cross-bridge formation between myosin and actin and contraction of the sarcomere. Cardiomyocyte relaxation is signaled by a return of intracellular [Ca2] to resting levels attributable to the following major mechanisms:(1) Cav1. 2 inactivation;(2) RyR2 inactivation;(3) Ca2 reuptake into the SR by SERCA2a pumps; and (4) Na/Ca2 exchange extrusion of Ca2 to the extracellular space. Under resting conditions, net SR Ca2 release contributes approximately 66% of Ca2 necessary for myofilament activation in large mammals including humans, and approximately 90% in rodents. 2